DOCSLIB.ORG

A Short Review of the Genes Involved in the Development and Progression of Colorectal Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Short Review of the Genes Involved in the Development and Progression of Colorectal Cancer BIOCELL Tech Science Press 2021 45(3): 483-487 A short review of the genes involved in the development and progression of colorectal cancer AMAYNA ZAKARIA; SYED ABDULLAH IBN ASADUZZAMAN; ZOBAYDA NAHAR; HAFSA JARIN SNIGDHA; TASKINA MURSHED; RASHED NOOR* Department of Life Sciences, School of Environment and Life Sciences, Independent University, Bangladesh (IUB), Dhaka, 1229, Bangladesh Key words: Colorectal cancer, Genes, Signal transduction pathways Abstract: The extent and aggression of colorectal cancer is a worldwide public health threat. Extensive research has been conducted on the pre-requisites leading to this fatal cancer. An array of genes along with their mutations and the signal transduction pathways leading to the cellular transformation into the cancerous cells have been investigated. Based on the knowledge gained so far, present review shortly discussed the role of the major genes especially those are involved in instigating abnormalities in the cellular cycles, cellular proliferation and differentiation. A simple but novel molecular scheme of the colorectal cancer development has also been plotted. Introduction within the right colon may trigger CRC (Medina Pabón and Babiker, 2020). On the contrary, in the case of HPCC-FAP, Defects in genomic organization have been linked to the hundreds or thousands of precancerous adenomatous polyps tumor progression have been suggested (defects in the form that, in turn, instigate the CRC (Medina Pabón and mitotic spindle leading to the formation of malignant Babiker, 2020). tumors) more than one hundred years ago; however, still Akin to the model of an adenoma probably induced by the research on cancer genetics ongoing with the aim of the DNA mutation due to environmental agent(s) or more finding the novel genes as well as the signal transduction specifically by the carcinogenic agents whose continuous pathways that are associated with the abnormal genetic impact resulting in the progression into a carcinoma constitution acquired as a result of mutation (Liu et al., (through a series of molecular signal transduction pathways, 2020; Forootan et al., 2019; Boveri, 1914). Colorectal cancers like the chromosomal instability pathway or CIN, the (CRCs) have long been known to develop through a cascade microsatellite instability pathway, MSI and the serrated of events (i.e., the adenoma-carcinoma sequence) starting adenoma pathway, etc.), the history of knowledge on (1) with the transformation of normal colonic epithelium to an The inherited susceptibilities of the colorectal adenomatous adenomatous intermediate and then ultimately polyps undergoing the malignant transformation (formation adenocarcinoma (Pino and Chung, 2010; Morson, 1974). of cancerous cells) and (2) The progressive research on the Familial adenomatous polyposis (FAP) along with the long-term risk of colorectal cancer is widely known syndromes not related to polyposis; for example, the Lynch effectively starting nearly 45 years ago continuing till date syndrome among the hereditary non-polyposis colorectal (Beggs and Hodgson, 2008; Hill et al., 1978; Muto et al., 1975). cancer (HNPCC), have been reported to be the most Indeed, the multistep genetic model of colorectal frequent cause for the development of the onset of carcinogenesis has been reported thirty years ago, which is hereditary colorectal cancer (HCRC), which is actually a still the accepted model for solid tumors (Fearon and group of syndromes, accounting up to 10% among all cases Vogelstein, 1990). According to the model, (1) The of CRCs including the hereditary polyposis colorectal cancer Adenomatous Polyposis Coli (APC) tumor suppressor gene (HPCC), so far reported (Medina Pabón and Babiker, 2020; is first inactivated, followed by the activation of mutations Valle et al., 2019). Among the HNPCC, the Lynch of the Kirsten rat sarcoma viral oncogene homolog or KRAS fl syndrome (LS) is the most common, whereby the at polyps (belongs to a class of oncogenes which, upon mutation, have the potential to transform normal cells into cancerous ones); *Address correspondence to: Rashed Noor, [email protected] (2) and the succeeding malignant transformation is Received: 22 October 2020; Accepted: 21 December 2020 propelled by the superfluous mutations in the transforming Doi: 10.32604/biocell.2021.014704 www.techscience.com/journal/biocell This work is licensed under a Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 484 AMAYNA ZAKARIA et al. growth factor-β (TGF-β) signaling pathway (involved in and hyperplastic polyposis syndrome (Beggs and Hodgson, cellular proliferation, differentiation, apoptosis, extracellular 2008; Sampson et al., 2005). matrix remodeling, angiogenesis, inflammation, etc.); (3) The commonest form of hereditary non-polyposis The phosphatidyl-inositol 3-kinase (PIK3) signaling colorectal cancer is the Lynch syndrome (also known as pathway boosts a major signaling pivot downstream of the Hereditary colorectal cancer syndrome), resulted due to the epidermal growth factor receptor and serves a key role in mutation of the DNA mismatch repair (MMR) enzymes the pathogenesis of several cancers), and (4) finally, the (which recognize and repair the flawed insertion, deletion, TP53 signaling pathways influence the cell cycle arrest, and mis-incorporation of the DNA bases during replication apoptosis, and angiogenesis (Pino and Chung, 2010; Fearon and recombination); i.e., (1) The mutation of hMSH2 gene and Vogelstein, 1990). The projection of the clinical concept (also known as the caretaker gene which encodes the DNA about colorectal cancer (CRC) is mainly based on the fact MMR protein, MSH2), (2) Human MutL homolog 1 or the that in relation to the size of the colon and rectum, tumors hMLH1 gene (whose mutation may lead to the missense are likely to be of larger size and eventually may pose a codons which in turn trim down the adeptness of MMR), higher cancer rate as measured by repeated colonoscopy, (3) hPMS1 gene (whose mutation may result in the sigmoidoscopy and polypectomy (Atkin et al., 1992). hereditary nonpolyposis colorectal cancer), (4) hPMS2 gene Deciphering the current state of knowledge on the genomics (also encoding the components of the DNA-mismatch of colorectal cancer including (1) The genetic changes in repair complex) and (5) The human mutS homolog 6 or the polyps undergoing the malignant transformation as well as hMSH6 gene which is also known as p160 (encodes the possible epigenomic changes in colorectal polyps; (2) the DNA MMR protein Msh6; and is the homologue of the Mechanism by which the key tumor suppressor gene APC human G/T binding protein, GTBP), is actually the early (adenomatous polyposis coli, whose product, the APC onset of colorectal cancer derived from colorectal protein, plays a grave role in several cellular processes) is endometrial, ovarian, gastric and urinary tract carcinoma mutated (leading to adenomatous polyposis, FAP or the (Lynch et al., 1988). attenuated FAP, i.e., AFAP) provoking colorectal The risk of colorectal carcinogenesis in the untreated carcinogenesis have long been a great interest for cancer FAP patients appears to be is 100%, while among the research (Beggs and Hodgson, 2008). Besides, a study on the attenuated APC variant (i.e., AAPC due to mutations in application of the gene expression profiles of cancer types/ the 3’ and 5’ end of the APC gene accompanied with the subtypes to detect the prognostic genes, as well their clinical mutation in the alternatively spliced exon 9) although implementations, is also going on (Liu et al., 2020). Based the risk remains the same, fewer polyps can be generated on the previous literature, the current review shortly in the late stage of life (Beggs and Hodgson, 2008). described the associated genes (as well as the mutation Interestingly, the FAP-like and AAPC-like phenotypes with points) and the relevant signal transduction pathways the absence of germline mutation in the APC gene have involved in the formation of colorectal cancer. been noticed to carry bi-allelic mutations of the MYH gene by 25% (Venesio et al., 2004). In the 1st–2nd decade of life, Genes Involved in the Development of Colorectal Cancer the Peutz-Jegher Syndrome (PJS) can be expressed which is characterized by the multiple hamartomatous polyps in the CRCs have been reported to develop along with long time gastrointestinal (GI) tract (Juvenile polyposis syndrome) due achieving successive accretion of genetic alterations to the germline mutation of the tumor suppressor gene oppressing (1) The regulators of cell proliferation, (2) The STK11, encoding a serine-threonine kinase which is known cell cycle mechanisms, (3) Apoptosis, and (4) The DNA to regulate the cell polarity, i.e., the cellular proliferation; repair system (Boland and Goel, 2010). The genome-wide and acts as a tumor suppressor (Beggs and Hodgson, 2008). sequencing projected around 80 mutated genes per Another tumor suppressor, known as the PTEN gene, colorectal tumor; however, nearly 15 among them were encoding the phosphatase and tensin homolog, has been pondered to be the major instigators of tumorigenesis (Pino reported to control the cell growth and proliferation, i.e., the and Chung, 2010; Leary et al., 2008; Wood et al., 2007). The regulation of cell cycle; preventing cells from growing and inherited colorectal cancer syndromes known as the familial dividing too rapidly, and to prevent
Load more

Recommended publications
  • BRCA1 in Hormonal Carcinogenesis: Basic and Clinical Research
    Endocrine-Related Cancer (2005) 12 533–548 REVIEW BRCA1 in hormonal carcinogenesis: basic and clinical research E M Rosen, S Fan and C Isaacs Department of Oncology, Lombardi Cancer Center, Georgetown University, 3970 Reservoir Road, NW, Washington, District of Columbia 20057, USA (Requests for offprints should be addressed to E M Rosen; Email: [email protected]) Abstract The breast and ovarian cancer susceptibility gene-1 (BRCA1) located on chromosome 17q21 encodes a tumor suppressor gene that functions, in part, as a caretaker gene in preserving chromosomal stability. The observation that most BRCA1 mutant breast cancers are hormone receptor negative has led some to question whether hormonal factors contribute to the etiology of BRCA1-mutant breast cancers. Nevertheless, the caretaker function of BRCA1 is a generic one and does not explain why BRCA1 mutations confer a specific risk for tumor types that are hormone- responsive or that hormonal factors contribute to the etiology, including those of the breast, uterus, cervix, and prostate. An accumulating body of research indicates that in addition to its well- established roles in regulation of the DNA damage response, the BRCA1 protein interacts with steroid hormone receptors (estrogen receptor (ER-a) and androgen receptor (AR)) and regulates their activity, inhibiting ER-a activity and stimulating AR activity. The ability of BRCA1 to regulate steroid hormone action is consistent with clinical-epidemiological research suggesting that: (i) hormonal factors contribute to breast cancer risk in BRCA1 mutation carriers; and (ii) the spectrum of risk-modifying effects of hormonal factors in BRCA1 carriers is not identical to that observed in the general population.
    [Show full text]
  • Functional Analysis of Novel Β-Catenin Mutants
    AN ABSTRACT OF THE THESIS OF Mohamed B. Al-Fageeh for the degree of Master of Science in Biochemistryand Biophysics presented on February 12, 2003. Title: Functional Analysis of Novel -catenin Mutants Abstract approved Redacted for privacy Roderick H. Dashwood 13-catenin is a multi functional protein that is involved in cell-cell adhesion and cell signaling. In non-stimulated cells,-catenin is tightly down-regulated by GSK-3dependent phosphorylation at Ser and Thr residues, followed by rapid ubiquitination and proteasomal degradation. It is well established that mutations within the regulatory GSK-313 region lead to stabilized13-catenin and constitutive f3-cateninlTCF-dependent gene activation. Furthermore, it has been shown that amino acids adjacent to codon 33, namely 32 and 34 of -catenin,are hotspots for substitution mutations in carcinogen-induced animaltumors. Thus, a major hypothesis of this thesis was that substitution mutations at codon 32 of13-catenin interfere with phosphorylation and ubiquitination of -catenin. Site-directed mutagenesis was used to create defined-catenin mutants, namely D32G, D32N, and D32Y. The signaling potential of various13-catenin was analyzed in a gene reporter assay by co-transfection witha hTcf eDNA with a reporter plasmid containing a Tcf-dependent promoter (TOPFlash). Therewas a significant enhancement of the reportergene activity with all [3-catenin mutants compared to WT t3-catenin after 48 hours of transfection. Protein analysisby Western blotting showed massive accumulation of mutant-catenin. Antibody specific for phosphorylated 13-catenin showed that the accumulated D32G and D32N 13-catenin proteins were strongly phosphorylated bothin vivoandin vitro, whereas D32Y 13-catenin exhibited significantly attenuated phosphorylationin vivo.
    [Show full text]
  • Original Article Gastrointestinal Stem Cells and Cancer
    Stem Cell Reviews Copyright © 2005 Humana Press Inc. All rights of any nature whatsoever are reserved. ISSN 15501550-8943/05/1:1–10/$30.00‐8943 / 05 / 1:233‐241 / $30.00 Original Article Gastrointestinal Stem Cells and Cancer— Bridging the Molecular Gap S.J. Leedham,*,1 A.T.Thliveris,2 R.B. Halberg,2 M.A. Newton,3 and N.A.Wright1 1Histopathology Unit, Cancer Research UK, 44 Lincoln’s Inn Fields, London WC2A 3PX,UK; 2McArdle Laboratory for Cancer Research, University of Wisconsin—Madison,Madison,WI 53706; and 3Department of Statistics, University of Wisconsin—Madison, Madison WI 53706 Abstract Cancer is believed to be a disease involving stem cells. The digestive tract has a very high cancer prevalence partly owing to rapid epithelial cell turnover and exposure to dietary toxins. Work on the hereditary cancer syndromes including famalial adenoma- tous polyposis (FAP) has led to significant advances, including the adenoma-carcinoma sequence. The initial mutation involved in this stepwise progression is in the “gate- keeper” tumor suppressor gene adenomatous polyposis coli (APC). In FAP somatic, second hits in this gene are nonrandom events, selected for by the position of the germ- line mutation. Extensive work in both the mouse and human has shown that crypts are clonal units and mutated stem cells may develop a selective advantage, eventually form- ing a clonal crypt population by a process called “niche succession.” Aberrant crypt foci are then formed by the longitudinal division of crypts into two daughter units—crypt fission. The early growth of adenomas is contentious with two main theories, the “top- down” and “bottom-up” hypotheses, attempting to explain the spread of dysplastic tissue in the bowel.
    [Show full text]
  • Stochastic Modelling of Tumorigenesis in P53 Deficient Mice
    British Joumal of Cancer (1998) 77(2), 243-252 © 1998 Cancer Research Campaign Stochastic modelling of tumorigenesis in p53 deficient mice JH Mao1, KA Lindsay2, A Balmain3 and TE Wheldon1'4 'Department of Radiation Oncology, University of Glasgow, CRC Beatson Laboratories, Garscube Estate, Glasgow G61 1 BD, UK; 2Department of Mathematics, University of Glasgow, University Gardens, Glasgow, UK; 3CRC Department of Medical Oncology, University of Glasgow, CRC Beatson Laboratories, Garscube Estate, Glasgow G61 1 BD, UK; 4Department of Clinical Physics, University of Glasgow and West Glasgow Hospitals University NHS Trust, Western Infirmary, Glasgow G 1 6NT, UK Summary Stochastic models of tumorigenesis have been developed to investigate the implications of experimental data on tumour induction in wild-type and p53-deficient mice for tumorigenesis mechanisms. Conventional multistage models in which inactivation of each p53 allele represents a distinct stage predict excessively large numbers of tumours in p53-deficient genotypes, allowing this category of model to be rejected. Multistage multipath models, in which a p53-mediated pathway co-exists with one or more p53-independent pathways, are consistent with the data, although these models require unknown pathways and do not enable age-specific curves of tumour appearance to be computed. An alternative model that fits the data is the 'multigate' model in which tumorigenesis results from a small number of gate-pass (enabling) events independently of p53 status. The role of p53 inactivation is as a rate modifier that accelerates the gate-pass events. This model implies that wild-type p53 acts as a 'caretaker' to maintain genetic uniformity in cell populations, and that p53 inactivation increases the probability of occurrence of a viable cellular mutant by a factor of about ten.
    [Show full text]
  • Bccipsuppresses Tumor Initiation but Is Required For
    Published OnlineFirst October 21, 2013; DOI: 10.1158/0008-5472.CAN-13-1766 Cancer Tumor and Stem Cell Biology Research BCCIP Suppresses Tumor Initiation but Is Required for Tumor Progression Yi-Yuan Huang, Li Dai, Dakim Gaines, Roberto Droz-Rosario, Huimei Lu, Jingmei Liu, and Zhiyuan Shen Abstract Dysfunctions of genome caretaker genes contribute to genomic instability and tumor initiation. Because many of the caretaker genes are also essential for cell viability, permanent loss of function of these genes would prohibit further tumor progression. How essential caretaker genes contribute to tumorigenesis is not fully understood. Here, we report a "hit-and-run" mode of action for an essential caretaker gene in tumorigenesis. Using a BRCA2- interacting protein BCCIP as the platform, we found that a conditional BCCIP knockdown and concomitant p53 deletion caused rapid development of medulloblastomas, which bear a wide spectrum of alterations involving the Sonic Hedgehog (Shh) pathway, consistent with a caretaker responsibility of BCCIP on genomic integrity. Surprisingly, the progressed tumors have spontaneously lost the transgenic BCCIP knockdown cassette and restored BCCIP expression. Thus, a transient downregulation of BCCIP, but not necessarily a permanent mutation, is sufficient to initiate tumorigenesis. After the malignant transformation has been accomplished and autonomous cancer growth has been established, BCCIP reverses its role from a tumor-initiation suppressor to become a requisite for progression. This exemplifies a new type of tumor suppressor, which is distinct from the classical tumor suppressors that are often permanently abrogated during tumorigenesis. It has major implica- tions on how a nonmutagenic or transient regulation of essential caretaker gene contributes to tumorigenesis.
    [Show full text]
  • Onc19 8REV 2..2
    Oncogene (2000) 19, 1059 ± 1064 ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00 www.nature.com/onc Role of the tumor suppressor gene Brca1 in genetic stability and mammary gland tumor formation Chu-Xia Deng*,1 and Frank Scott1 1Genetics of Development and Disease Branch, 10/9N105, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, MD 20892, USA Germline mutations in the tumor suppressor BRCA1 The BRCA1 gene contains 24 exons, which encode a predispose women to breast and ovarian cancers. Current large protein of 1863 amino acids in humans and 1812 evidence demonstrates that mutations in BRCA1 do not amino acids in mice (Bennett et al., 1995; Lane et al., directly result in tumor formation, but instead cause 1995; Marquis et al., 1995; Miki et al., 1994). It also genetic instability, subjecting cells to high risks of contains a number of motifs that may have distinct malignant transformation. In an animal model in which functions [reviewed in (Paterson, 1998), and Figure 1]. Brca1 is mutated speci®cally in mammary epithelium, The zinc ®nger domain in the amino terminus interacts tumorigenesis occurs in mutant glands at low frequency with DNA directly or indirectly through protein ± after a long latency. Notably, introduction of a p53-null protein interactions (Jin et al., 1997; Wu et al., 1996). allele signi®cantly enhanced mammary gland tumor The carboxyl terminus contains a BRCT domain, formation in Brca1 conditional mutant mice. These which is a relatively common feature of proteins results are consistent with a model that Brca1 is a involved in DNA damage response checkpoints (Bork caretaker gene, whose absence causes genetic instability et al., 1997).
    [Show full text]
  • Bccipsuppresses Tumor Initiation but Is Required for Tumor Progression
    Published OnlineFirst October 21, 2013; DOI: 10.1158/0008-5472.CAN-13-1766 Cancer Tumor and Stem Cell Biology Research BCCIP Suppresses Tumor Initiation but Is Required for Tumor Progression Yi-Yuan Huang, Li Dai, Dakim Gaines, Roberto Droz-Rosario, Huimei Lu, Jingmei Liu, and Zhiyuan Shen Abstract Dysfunctions of genome caretaker genes contribute to genomic instability and tumor initiation. Because many of the caretaker genes are also essential for cell viability, permanent loss of function of these genes would prohibit further tumor progression. How essential caretaker genes contribute to tumorigenesis is not fully understood. Here, we report a "hit-and-run" mode of action for an essential caretaker gene in tumorigenesis. Using a BRCA2- interacting protein BCCIP as the platform, we found that a conditional BCCIP knockdown and concomitant p53 deletion caused rapid development of medulloblastomas, which bear a wide spectrum of alterations involving the Sonic Hedgehog (Shh) pathway, consistent with a caretaker responsibility of BCCIP on genomic integrity. Surprisingly, the progressed tumors have spontaneously lost the transgenic BCCIP knockdown cassette and restored BCCIP expression. Thus, a transient downregulation of BCCIP, but not necessarily a permanent mutation, is sufficient to initiate tumorigenesis. After the malignant transformation has been accomplished and autonomous cancer growth has been established, BCCIP reverses its role from a tumor-initiation suppressor to become a requisite for progression. This exemplifies a new type of tumor suppressor, which is distinct from the classical tumor suppressors that are often permanently abrogated during tumorigenesis. It has major implica- tions on how a nonmutagenic or transient regulation of essential caretaker gene contributes to tumorigenesis.
    [Show full text]
  • The Relationship Between Aging and Carcinogenesis: a Critical Appraisal
    Critical Reviews in Oncology/Hematology 45 (2003) 277Á/304 www.elsevier.com/locate/critrevonc The relationship between aging and carcinogenesis: a critical appraisal Vladimir N. Anisimov * Department of Carcinogenesis and Oncogerontology, N.N. Petrov Research Institute of Oncology, Pesochny-2, 68 Leningradskaya St., St. Petersburg 197758, Russia Accepted 11 September 2002 Contents 1. Introduction ............................................. 278 2. Age-related increase in spontaneous tumor development . ................. 278 3. Is the susceptibility to carcinogenesis similar in different tissues at different age ....... 279 4. Aging and multi-stage carcinogenesis ............................... 280 5. Cellular senescence and carcinogenesis .............................. 284 6. Do carcinogens accelerate aging .................................. 286 7. Do premature aging promote carcinogenesis ........................... 289 8. Effect of genetic modifications of aging on carcinogenesis . ................. 290 9. Oxidative stress in aging and carcinogenesis ........................... 293 10. Life span extension and risk of cancer .............................. 293 11. Conclusions ............................................. 297 12. Reviewers .............................................. 297 Acknowledgements ............................................ 297 References ................................................. 297 Biography ................................................. 304 Abstract The incidence of cancer increases with age in
    [Show full text]
  • The Expression and the Nuclear Activity of the Caretaker Gene Ku86 Are Modulated by Somatostatin
    ORIGINAL PAPER The expression and the nuclear activity of the caretaker gene ku86 are modulated by somatostatin S. Pucci,1 E. Bonanno,1 F. Pichiorri,1 P. Mazzarelli,2 L.G. Spagnoli1 1Dept. of Biopathology, University of Rome “Tor Vergata”, Rome; 2Dept. of Dermatology, University of Naples ”Federico II”, Naples, Italy omatostatin (SST) is a peptide hormone, ©2004, European Journal of Histochemistry which plays an important regulatory role in Somatostatin is a peptide hormone that exerts antisecretory Sthe endocrine, paracrine and autocrine secre- and antiproliferative activities on some human tumors. The tions of several anterior pituitary, and gastrointesti- Ku70/86 heterodimer acts as regulatory subunit of the DNA dependent protein kinase and its DNA binding activity medi- nal hormones. ates DNA double strands breaks repair that is crucial to Besides, it has been shown that SST exerts an maintain the genetic integrity of the genome. The activation antiproliferative activity on some human cancer of the heterodimer regulates cell cycle progression and the activity of nuclear transcription factors involved in DNA repli- including breast cancer,pancreatic cancer,small cell cation and cell proliferation. Moreover Ku86 behaves as a lung carcinoma and neuroblastoma (De Vita et al., receptor for the growth inhibitory tetradecapeptide, somato- 1997). The biological activity of this peptide is statin. Herein we report that somatostatin treatment to a dependent on its interaction with specific receptors, colon carcinoma cell line (Caco-2) inhibits cell growth and, at same time, strongly modulates the activation of Ku70/86 whose structures have recently been elucidated by heterodimer and the levels of Ku86 in the nucleus by means of cloning experiments (Yamada et al., increasing its specific mRNA level.
    [Show full text]
  • Multistage Carcinogenesis and the Incidence of Colorectal Cancer
    Multistage carcinogenesis and the incidence of colorectal cancer E. Georg Luebeck* and Suresh H. Moolgavkar Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, P.O. Box 19024, Seattle, WA 98109-1024 Edited by Alfred G. Knudson, Jr., Institute for Cancer Research, Philadelphia, PA, and approved September 11, 2002 (received for review February 27, 2002) We use general multistage models to fit the age-specific incidence ACF, also referred to as adenomatous crypts or microadenoma, of colorectal cancers in the Surveillance, Epidemiology, and End frequently show loss of heterozygosity on 5q, the locus of the Results registry, which covers Ϸ10% of the U.S. population, while adenomatous polyposis coli (APC) gene (14–17). ACF are simultaneously adjusting for birth cohort and calendar year effects. believed to be precursors to the adenomatous polyps, which in The incidence of colorectal cancers in the Surveillance, Epidemiol- turn are widely believed to be precursor lesions for colon ogy, and End Results registry is most consistent with a model carcinoma. The transition from adenoma to high-grade dysplasia positing two rare events followed by a high-frequency event in the (HGD) appears to involve the TP53 gene, considered a guardian conversion of a normal stem cell into an initiated cell that expands of the genome (12). Once HGD occurs, it has been suggested clonally to give rise to an adenomatous polyp. Only one more rare that ‘‘genetic chaos’’ ensues, setting the stage for malignant event appears to be necessary for malignant transformation. The transformation (18). two rare events involved in initiation are interpreted to represent Important insights into age effects and temporal trends in the homozygous loss of adenomatous polyposis coli gene function.
    [Show full text]
  • BRCA1 Induces Antioxidant Gene Expression and Resistance to Oxidative Stress
    [CANCER RESEARCH 64, 7893–7909, November 1, 2004] BRCA1 Induces Antioxidant Gene Expression and Resistance to Oxidative Stress Insoo Bae,1 Saijun Fan,1 Qinghui Meng,1 Jeong Keun Rih,1 Hee Jong Kim,1 Hyo Jin Kang,1 Jingwen Xu,1 Itzhak D. Goldberg,2 Anil K. Jaiswal,3 and Eliot M. Rosen1 1Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC; 2Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus for the Albert Einstein College of Medicine, New Hyde Park, New York; and 3Department of Pharmacology, Baylor College of Medicine, Houston, Texas ABSTRACT binding protein), retinoblastoma 1, retinoblastoma 1-associated pro- teins (RbAp46/48), and several histone deaceylases (HDAC-1/2)], Mutations of the breast cancer susceptibility gene 1 (BRCA1), a tumor and/or sequence-specific DNA-binding transcription factors (e.g., suppressor, confer an increased risk for breast, ovarian, and prostate p53, c-Myc, estrogen receptor, and other proteins; refs. 7–12). cancers. To investigate the function of the BRCA1 gene, we performed DNA microarray and confirmatory reverse transcription-PCR analyses to Some of the functions of BRCA1 cited above may be due, in part, identify BRCA1-regulated gene expression changes. We found that to regulation of specific transcriptional pathways by BRCA1, but the BRCA1 up-regulates the expression of multiple genes involved in the linkage of these functions to BRCA1-regulated transcription is not cytoprotective antioxidant response, including glutathione S-transferases, well understood. We used cell culture models of BRCA1 overexpres- oxidoreductases, and other antioxidant genes. Consistent with these find- sion, underexpression, and mutational inactivation to identify patterns ings, BRCA1 overexpression conferred resistance while BRCA1 deficiency of BRCA1-regulated gene expression.
    [Show full text]
  • 1 the Origin of Genome Instability in Cancer
    The Origin of Genome Instability in Cancer: Role of the Fragile Site Gene Product FHIT Dissertation Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Joshua Charles Saldivar, M.S. Biomedical Sciences Graduate Program The Ohio State University 2013 Dissertation Committee: Kay Huebner, PhD, Advisor Carlo Croce, MD Joanna Groden, PhD Denis Guttridge, PhD 1 Copyright by Joshua Charles Saldivar 2013 2 ABSTRACT The transformation of normal cells to cancer cells involves multiple steps mediated by the acquisition of mutations, selection and clonal expansion of cells with favorable mutations. Most cancers exhibit remarkable genomic instability, defined as an elevated rate of genetic mutation at the single nucleotide and chromosome levels. Genomic instability is a facilitating hallmark of cancer in that it raises the probability of generating cancer-promoting mutations. Multiple factors contribute to the genome instability phenotypes seen in cancer, but the molecular processes initiating instability in sporadic cancer are unknown. In dysplastic cells, genomic alterations are first seen at chromosome fragile sites. These fragile sites are exquisitely sensitive to agents that stress DNA replication forks, and thus, it is thought that replicative stress is a major source of genome instability in cancer. A frequent and very early genetic alteration in precancerous cells is deletion within fragile site FRA3B, which overlaps exons of the large FHIT gene, resulting in loss of FHIT protein expression. Here it is shown that loss of FHIT expression triggers endogenous replication stress hindering replication fork progression and inducing fork stalling and collapse.
    [Show full text]